Two cases of cutaneous gnathostomiasis after eating raw Salangichthys microdon (icefish, shirauo).

Cutaneous gnathostomiasis (CG) is a disease caused by ingestion of third-stage Gnathostoma larva in raw snakes, freshwater fish or frogs. The common causative organisms of CG in Japan include G. nipponicum, G. spinigerum, G. doloresi, G. binucleatum and G. hispidum. We report two cases of CG after eating many raw Japanese icefishes (Salangichthys microdon). In both cases, linear itchy eruptions on the trunk developed after eating many S. microdon. We performed genetic analysis in the first case, which revealed G. nipponicum. Of note, this is the first case of CG diagnosed based on genetic analysis in Japan. In Japan, eating whole small raw freshwater fish is common. The most popular types of raw small freshwater fish consumed in Japan are S. microdon (shirauo in Japanese) and Leucopsarion petersii (shirouo in Japanese). Usually, S. microdon are born in rivers, but live in both the sea and rivers. They feed on small fish and freshwater water fleas and spawn in rivers in the spring. On the other hand, L. petersii are born in rivers, but move to the sea soon after hatching. They feed on plankton such as copepod in the sea. They do not feed on anything when they return to rivers to spawn in the spring. Therefore, we hypothesize that S. microdon are more easily parasitized by G. nipponicum.

Elderly-Onset Generalized Pustular Psoriasis without a Previous History of Psoriasis Vulgaris.

Generalized pustular psoriasis (GPP) is characterized by sudden fever and extensive erythema with pustules and occurs in patients with or without preceding psoriasis vulgaris. We report an 83-year-old man showing irregularly shaped erythema with pustules on the trunk and extremities. He initially had no fever and came to our clinic a few days after the onset of the skin lesions because of high fever and general malaise. We found an extension and new development of erythema and pustules on the whole body. The patient also manifested night delirium. Histological examination revealed neutrophil infiltration into the upper epidermis, which formed a spongiform pustule of Kogoj. Pustular fluid cultures were negative for bacteria. We diagnosed GPP without preceding psoriasis vulgaris. Mutation analysis revealed no significant mutations in IL36RN and CARD14. Previous reports indicated that onset of GPP at the age of 83 years is definitely rare. In older individuals, general disease characteristics include an atypical clinical course, an especially slow appearance and cure, and mental disorder. Our case also revealed such characteristics. Thus, it is necessary to be aware of the clinical course and mental problems in elderly patients with GPP.

Blue Rubber Bleb Nevus Syndrome Showing Vascular Skin Lesions Predominantly on the Face.

An 81-year-old Japanese man presented with dark blue papules and nodules on his face. There were multiple soft papules and nodules, dark blue in color, compressive, and ranging in size from 2 to 10 mm. A few similar lesions were seen on the patient's right dorsal second toe and right buccal mucosa. There were no skin lesions on his trunk and upper limbs. The patient's past history did not include gastrointestinal bleeding or anemia. Histopathological examination showed dilated vascular spaces lined by the normal epithelium extending beneath the dermis and into the subcutaneous fat. Endoscopy of the gastrointestinal tract to check for colon involvement was not performed. X-ray images of the limbs revealed no abnormalities in the bones or joints. Laboratory investigations did not show anemia. Although we failed to confirm a diagnosis by endoscopy, the skin lesions, histopathological findings, lack of abnormal X-ray findings, and the presence of oral lesions as a part of gastrointestinal tract guided the diagnosis of blue rubber bleb nevus syndrome (BRBNS). Skin lesions of BRBNS occur predominantly on the trunk and upper limbs. However, the present case showed multiple skin lesions predominantly on the face. Therefore, it is important for clinicians to know about a possible atypical distribution of skin lesions in BRBNS.

Oral lichen planus with antibodies to desmogleins 1 and 3.

Lichen planus (LP) is a chronic inflammatory disorder involving the skin or mucous membranes. Previous studies have demonstrated that some LP patients showed positive enzyme-linked immunosorbent assay (ELISA) for desmoglein (DSG) antibodies. We report a case with intractable painful oral lesions. ELISA indices for DSG1 and 3 antibodies were increased by 49 and 36, respectively. Histopathological analysis revealed irregular acanthosis and band-like infiltration of lymphocytes at the dermal-epidermal interface. Direct immunofluorescence revealed negative deposits of immunoglobulin G and C3 in intracellular spaces of the epidermis. Indirect immunofluorescence of normal skin also did not detect any antibodies. Consequently, we made a final diagnosis of oral LP. The previous two LP cases with positive ELISA for DSG antibodies and our case manifested the erosive form, the most advanced oral LP. Therefore, it is a possibility that severe damage of keratinocytes may induce generation of DSG antibodies. However, negative results of immunofluorescence and no relation between disease severity and titers of antibodies make the possibility unlikely. We should measure titers of DSG antibodies in LP patients and accumulate data to establish a valid conclusion.

Functional analysis of the nuclear localization signal of the POU transcription factor Skn­1a in epidermal keratinocytes.

POU domain proteins are a family of critical regulators of development and differentiation due to their transcriptional activity in the nucleus. Skn­1a, a member of the POU domain protein family, appears to be expressed predominantly in epidermal keratinocytes and is thought to play a critical role in keratinocyte differentiation and proliferation. In this study, we examined the mechanisms involved in the nuclear localization of Skn­1a. We transiently expressed enhanced green fluorescent protein (EGFP) reporter constructs encoding EGFP fusions with Skn­1a deletion and mutation proteins in normal human epidermal keratinocytes (NHEKs). The experiments clearly demonstrated that Skn­1a contained a functional nuclear localization signal (NLS) domain, and that the smallest domain necessary for Skn­1a nuclear transport was the GRKRKKR sequence located within amino acids 279­285. Previous studies have shown that the phosphorylation of specific amino acids neighboring the NLS may regulate nuclear transport and that the amino acid residues threonine (Thr) and serine (Ser) have the potential to undergo phosphorylation. We examined whether the amino acids Thr286 and Ser287, which reside adjacent to the NLS at the carboxy­terminal side, play a role in Skn­1a nuclear localization. For this purpose, we generated three EGFP­Skn­1a mutation constructs, in which Thr286, Ser287, or both Thr286 and Ser287 residues were replaced with alanine, respectively. The results showed that the Thr286 and Ser287 residues were involved in the regulation of nuclear localization as well as epidermal differentiation. These results suggested that the epidermal differentiation signaling pathway, involving kinase and phosphatase activation, may regulate the NLS activity of Skn­1a in keratinocytes. Collectively, these data contribute to understanding the mechanisms of nuclear translocation of POU domain proteins and epidermal differentiation.

Signet-ring cutaneous squamous cell carcinoma arising on the back of the finger.

A variety of pathologic variants of cutaneous squamous cell carcinoma (SCC) has been reported, and the signet-ring variant of cutaneous SCC is extremely uncommon. We reported an 83-year-old man with signet-ring SCC arising on the back of the finger. As far as we know, only 4 cases have been described in detail, and one dermatopathologic report focused on the presence of signet-ring cells briefly described in clinical data of 6 cases. Interestingly, in these reports, the skin lesions of 10 cases occurred exclusively in the head and neck area. This case involved a skin lesion on the back of the finger and is thus the first reported case of signet-cell cutaneous SCC that did not arise in the head and neck area. The location of this lesion, together with the histological findings compatible with actinic keratosis, support the hypothesis that the development of signet-ring SCC is related to ultraviolet light-induced damage.

Multiple aplasia cutis congenita lesions located along Blaschko's lines in a patient with tetralogy of Fallot-A.

BACKGROUND: Aplasia cutis congenita (ACC) is a congenital absence of skin, and a single alopecic lesion on the scalp is the most common form. MAIN OBSERVATION: We present a case of ACC with tetralogy of Fallot-A. Differetial diagnosis included Adams-Oliver syndrome and nevus psiloliparus. Interestingly, our patient showed multiple ACC lesions, which were located along Blaschko's lines. CONCLUSIONS: As far as we know, our case is the third case of ACC with tetralogy of Fallot-A. Also, this is the first case of ACC associated with Blaschko's lines.

Dermoscopy of eccrine poroma with calcification.

BACKGROUND: Eccrine poromas are relatively common slow-growing benign solitary adnexal tumors originating from the intraepidermal portion of the eccrine sweat duct (acrosyringium). Dystrophic calcification is rarely found in lesions of eccrine poroma, and only 2 cases of eccrine poroma with calcification have been reported thus far. In the present report, we describe another case of eccrine poroma with calcification occurring in the palm of the hand. Also, we show dermoscopic features of this case. MAIN OBSERVATIONS: A 73-year-old man with hemiparesis, who had a 10-year history of tumor on his right palm, which was occasionally injured by a walking crutch, causing bleeding and ulceration. Physical examination revealed a pigmented dome-shaped tumor. Dermoscopic analysis revealed glomerular vessels, multiple pink-white structureless areas, and lacunae. Histological examination revealed that the tumor was composed of cords of tumor cells extending from the epidermis into the dermis. These were uniformly cuboidal cells with round, basophilic nuclei and dense vascular stromas with telangiectasia. The tumor showed cystic structures and calcification. The patient was diagnosed with Pinkus-type eccrine poroma on the basis of histological findings. CONCLUSIONS: Although cutaneous neoplasms commonly associated with calcification are of follicular origin, it is known that dystrophic calcification may be triggered also in tumors of eccrine origin by multiple factors, including mechanical injury. Dermoscopy may be helpful in establishing clinical diagnosis of calcified eccrine poromas.

Significance of sentinel node biopsy in the management of squamous cell carcinoma arising from recessive dystrophic epidermolysis bullosa.

The most life-threatening complication developing in patients with recessive dystrophic epidermolysis bullosa (RDEB) is squamous cell carcinoma (SCC). To improve patient prognosis, early detection of regional lymph node metastasis is required. Herein, we report a patient diagnosed with non-Hallopeau-Siemens RDEB who developed SCC on the left foot with inguinal lymph node swelling. Use of the sentinel node biopsy (SNB) technique favorably minimized defective damage to the inguinal region in this case. Genetic analysis identified one novel COL7A1 mutation, a maternal c.238G > C (p.A80P) and one previously reported mutation, a paternal c.3631C > T (p.Q1211X). A published work review demonstrated that no COL7A1 mutations specific for SCC development in RDEB have previously been identified. It remains unclear if SNB in combination with gene diagnosis is beneficial for the management of SCC in RDEB patients, however, because of the limited number of case reports. To address this issue, COL7A1 mutational analysis should be performed in as many cases of RDEB as possible.

Papillon-Lefèvre syndrome and malignant melanoma. A high incidence of melanoma development in Japanese palmoplantar keratoderma patients.

Papillon-Lefèvre syndrome (PLS) is a rare autosomal-recessive genodermatosis characterized by palmoplantar hyperkeratosis and severe early-onset periodontitis. The development of malignant cutaneous neoplasms within the hyperkeratotic lesions of the syndrome is quite rare. Here, we report on a 51-year-old Japanese woman with PLS associated with recurrent malignant melanoma (MM). Mutation analysis of the cathepsin C gene revealed that the proband was homozygous for a missense mutation, c.415G-->A, which is predicted to result in the amino acid substitution p.G139R. Including our case, 4 families have been described as having PLS with MM, 3 of which are Japanese, implying a high incidence of melanoma development in Japanese PLS patients. We suggest that hereditary palmoplantar keratoderma (PPK) in Japanese patients might be predisposed to MM. A literature review revealed that in 18 cases of MM-associated PPK, 13 (76%) were Japanese, suggesting a high incidence of MM in Japanese PPK patients. This tendency might be attributable to the high frequency of acral lentiginous melanoma in Japanese subjects, in contrast to a lower frequency of this subtype in Caucasians.

Calcineurin/NFAT-dependent regulation of 230-kDa bullous pemphigoid antigen (BPAG1) gene expression in normal human epidermal keratinocytes.

BACKGROUND AND OBJECTIVE: Cyclosporin A (CsA) is utilized widely for treatment of inflammatory skin diseases, such as psoriasis vulgaris. The therapeutic effects of CsA are thought to be mediated by its immunosuppressive action on infiltrating lymphocytes in the lesional skin. CsA also inhibits epidermal keratinocyte proliferation, suggesting a direct biological action on keratinocytes. Here we tested the hypothesis that CsA can modulate the expression of the nuclear factor of activated T-cell (NFAT) in epidermal keratinocytes. We also investigated whether the keratinocyte-specific gene expression is modified by CsA through NFAT activity in association with differentiation induction. METHODS: RT-PCR was performed using total RNAs extracted from cultured normal human epidermal keratinocytes (NHEK), normal human dermal fibroblasts (NHDF), and normal human epidermal melanocytes (NHEM) for detecting NFAT isomolecules. Transient transfections of NHEK with a 230-kDa bullous pemphigoid antigen (BPAG1) promoter/luciferase reporter gene and the luciferase assay were conducted for examining the effect of CsA on the promoter activity of the BPAG1 gene. Electrophoretic gel mobility shift assays (EMSA) with probes containing NFAT consensus sequences for analyzing the binding activities of the nuclear proteins extracted from NHEK. RESULTS: RT-PCR revealed expression of all of the five isoforms of NFAT in the cell lines examined. The mRNA expression levels of NFAT1, NFAT2, BPAG1, and involucrin were downregulated by CsA treatment in NHEK. The luciferase assay indicated suppression of the promoter activity by CsA. EMSA with NFAT consensus probes identified in the BPAG1 promoter region demonstrated specific binding activity in the nuclear proteins of epidermal keratinocytes. CONCLUSION: As reported previously, our results indicate that epidermal keratinocytes possess calcineurin/NFAT system, which is suppressed by CsA. In addition, the data suggest that CsA can downregulate the BPAG1 gene expression perhaps via the NFAT consensus cis-elements in the BPAG1 promoter region. Such transcriptional regulatory system might be involved in the regulation of keratinocyte differentiation and proliferation.

A case of bullous dermatitis artefacta possibly induced by a deodorant spray.

Dermatitis artefacta is one of a spectrum of factitious diseases etiologically responsible for skin lesions denied by patients. These factors often make it difficult to identify the causative agents of the condition. Herein, we report a case of bullous dermatitis artefacta in a 12-year-old girl, for which a deodorant spray was suspected as the probable cause. Pathological examination revealed subepidermal blistering with full-thickness necrosis of the epidermis, suggesting a thermo- or cryo-induced injury. Psychological testing demonstrated her immaturity and dependence. In searching for the causative agent, we suspected a deodorant spray as a blister-inducing agent. We succeeded in reproducing a similar blister lesion on the volunteer's healthy skin using the same spray. Psychiatric involvement significantly complicates the treatment of factitious diseases, including dermatitis artefacta. Cooperation among dermatologists, psychiatrists and the patient's family members is required for ensuring a favorable prognosis.

Human metallothionein gene expression is upregulated by beta-thujaplicin: possible involvement of protein kinase C and reactive oxygen species.

Recently, we discovered that beta-thujaplicin (BT) induces metallothionein (MT) expression in mouse keratinocytes, both in vivo and in vitro. However, the molecular mechanisms by which BT exerts its biological effects have not been elucidated. The purpose of this study is to explore the signal transduction pathway involved in the MT mRNA induction by BT. Using a HaCaT keratinocyte cell line, Northern blotting was performed for analyzing the human MT-IIA mRNA expression levels in combination with BT and a number of protein kinase (PK) inhibitors including H7, HA1004 and a PKC-specific inhibitor chelerythrin. CAT assays with the MT-IIA gene promorter-CAT construct were conducted for examining the transcriptional regulation by BT of MT. A free radical scavenger N-acetylcysteine (NAC) was used for analyzing a role of oxidative stress for the MT gene induction by BT. BT increased MT-IIA gene transcript levels and CAT activity in a dose-dependent fashion in HaCaT cells. The increase in MT-IIA mRNA levels and CAT activity were completely suppressed by H7 but not by HA1004. In addition, chelerythrin prevented BT-inducible MT-IIA promoter activation. Furthermore, NAC suppressed BT-inducible MT-IIA promoter activation. These results demonstrate that BT is a potent activator of the MT-IIA gene promoter and that PKC activation and reactive oxygen species are implicated in BT-inducible MT-IIA gene expression. BT may be a useful tool for dissecting the signal transduction pathway mediating MT-IIA promoter activation.